Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P33/00—Antiparasitic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the invention described herein relates to compounds useful as medicaments, particularly derivatives of camptothecin with structural modifications of the lactone ring, to processes for their preparation, to their use as active agents endowed with topoisomerase I inhibiting activity and to pharmaceutical compositions containing them as active ingredients.
• Camptothecin is an alkaloid isolated by Wall et al. (J. Am. Chem. Soc, 88, 3888-3890 (1966)) for the first time from the tree Camptotheca acuminata, a plant native to China, belonging to the Nyssaceae family.
• the molecule consists of a pentacyclic structure with a lactone in the E ring, which is essential for cytotoxicity.
• lactone ring which is a portion of the molecule essential for the camptothecins to be able to exercise their pharmacological activity
• stability of the ring itself which, in turn, is responsible for the half-life of the drug.
• the ⁇ -hydroxylactone structure is defined as a lactone that involves the presence of a supplementary carbon atom between the carboxyl carbon atom and the carbon atom in ⁇ - bearing the hydroxy in the ⁇ -hydroxylactone structure.
• substituents on the supplementary carbon atom and the substituents indicated are the lower alkyls together with the lower alkoxy, halogen or hydroxy. In the patent application mentioned no evidence of improved stability of the lactone ring is provided.
• substituted 7-oxime camptothecins with a modified lactone ring, are endowed with substantial anticancer activity and are stable in plasma. These compounds have a better therapeutic index.
• Ri is hydrogen or a -C(R5)-N-0-R 4 group, in which R is hydrogen or a straight or branched C1-C5 alkyl or C1-C5 alkenyl group, or a C ⁇ -Cio cycloalkyl group, or a straight or branched (C3-C10) cycloalkyl - (Ci-Cs) alkyl group, or a C6-C14 aryl group, or a straight or branched (C6-C14) aryl - (C1-C5) alkyl group, or a heterocyclic group or a straight or branched heterocyclo - (C1-C5) alkyl group, said heterocyclic group containing at least one heteroatom selected from an atom of nitrogen, optionally substituted with an (C1-C5) alkyl group, and/or an atom of oxygen and/or of sulphur; said alkyl, alkenyl, cycloalkyl, cycloal
• R 4 is a (C ⁇ -Cio) aroyl or (C ⁇ -Cio) arylsulphonyl residue, optionally substituted with one or more groups selected from: halogen, hydroxy, straight or branched C1-C5 alkyl, straight or branched C1-C5 alkoxy, phenyl, cyano, nitro, -NR10R11, where Rio and R ⁇ , which may be the same or different, are hydrogen, straight or branched C1-C5 alkyl; or: R 4 is a polyaminoalkyl residue; or
• R is a glycosyl residue
• R5 is hydrogen, straight or branched C1-C5 alkyl, straight or branched C1-C5 alkenyl, C3-C10 cycloalkyl, straight or branched (C3-C10) cycloalkyl - (C1-C5) alkyl, C ⁇ -C aryl, straight or branched (C ⁇ -G ) aryl - (C ⁇ -C 6 ) alkyl;
• R2 and R3 which may be the same or different, are hydrogen, hydroxy, straight or branched C1-C5 alkoxy;
• n 1 or 2
• Z is selected from hydrogen, straight or branched C1-C4 alkyl
• Ni-oxides the racemic mixtures, their individual enantiomers, their individual diastereoisomers, their mixtures, and their pharmaceutically acceptable salts, with the proviso that, in formula (I), Ri, R2 and R3 cannot be simultaneously hydrogen.
• the present invention includes the use of compounds of the above- mentioned formulae (I) and (II) as active ingredients for medicaments, particularly for medicaments which are useful as topoisomerase I inhibitors.
• active ingredients for medicaments, particularly for medicaments which are useful as topoisomerase I inhibitors.
• the present invention includes pharmaceutical compositions containing compounds of formula (I) and/or formula (II) as active ingredients, in admixture with pharmaceutically acceptable vehicles and excipients.
• the present invention also includes the processes for the preparation of compounds of formula (I) and (II), and the key intermediate products.
• examples of the straight or branched C1-C5 alkyl group are understood to include methyl, ethyl, propyl, butyl, pentyl and their possible isomers, such as, for example, isopropyl, isobutyl, and ter-butyl.
• Examples of the branched or straight C1-C5 alkenyl group are methylidene, ethylidene, vinyl, allyl, propargyl, butylene, and pentylene, where the double carbon-carbon bond may be situated in the various possible positions of the alkylene ring, which can also be branched in the context of the isomery allowed.
• Examples of the C3-C10 cycloalkyl group are cyclopropyl, cyclobutyl, cyelopentyl, cyclohexyl, cyclooctyl, and polycyclic groups, such as, for example, adamantyl.
• Examples of the straight or branched (C3-C10) cycloalkyl - (C1-C5) alkyl group are cyclopropylmethyl, 2-cyclopropylethyl, 1 -cyclop ropylethyl, 3- cyclopropylpropyl, 2-cyclopropylpropyl, 1-cyclopropylpropyl, cyclo- butylmethyl, 2-cyclobutylethyl, 1-cyclobutylethyl, 3-cyclobutylpropyl, 2-cyclobutylpropyl, 1-cyclobutylpropyl, cyclohexylmethyl, 2-cyclo- hexylethyl, 1-cyclohexylethyl, 3-cyclohexylpropyl, 2-cyclohexylpropyl, 1-cyclohexylpropyl, 5-cyclohexylpentyl, 3-cyclohexylpentyl, 3-methyl-2- cyclohex
• Examples of the straight or branched (C6-C14) aryl or (C ⁇ -Cu) aryl - (Ci- C5) alkyl group are phenyl, 1- or 2-naphthyl, anthracenyl, benzyl, 2- phenylethyl, 1-phenylethyl, 3-phenylpropyl, 2-anthracenylpropyl, 1- anthracenylpropyl, naphthylmethyl, 2-naphthylethyl, 1-naphthylethyl, 3-naphthyl-propyl, 2-naphthylpropyl, 1-naphthylpropyl, cyclohexylmethyl, 5-phenylpentyl, 3-phenylpentyl, 3-methyl-2-phenylbutyl.
• Examples of the straight or branched heterocyclic or heterocyclo - (Ci- C5) alkyl group are thienyl, quinolyl, pyridyl, N-methylpiperidinyl, 5- tetrazolyl, 2-(4,5-dihydroxazolyl), l,2,4-oxadiazolidin-3-yl-5-one, purine and pyrimidine bases, e.g. uracyl, optionally substituted as indicated in the general definitions above.
• Examples of the (Ce-Cio) aroyl groups are benzoyl and naphthoyl.
• Examples of the (C ⁇ -Cio) arylsulphonyl groups are tosyl and benzoylsulphonyl.
• halogen is fluorine, chlorine, bromine and iodine.
• substituted groups are pentafluorophenyl, 4-phenyl- benzyl, 2,4-difl.uorobenzyl, 4-aminobutyl, 4-hydroxybutyl, dimethyl- aminoethyl, p-nitrobenzoyl, p-cyanobenzoyl.
• polyaminoalkyl residue is -(CH2)m-NRi2-(CH_2) P - NR 1 3-(CH2)q-NH2, where m, p and q are whole numbers from 2 to 6 inclusive and R12 and R13 are a straight or branched (C1-C5) alkyl group, for example 4-aminobutyl-2-aminoethyl, 3-amino-propyl-4- aminobutyl, 3-aminopiOpyl-4-aminobutyl-3-aminopropyl.
• glycosyl residue 6-D-galactosyl and 6-D-glucosyl.
• salts with pharmaceutically acceptable acids are, in the case of atoms of nitrogen of a basic nature, salts with pharmaceutically acceptable acids, both inorganic and organic, such as, for example, hydrochloric acid, sulphuric acid, acetic acid, or, in the case of an acid group, such as carboxyl, salts with pharmaceutically acceptable bases, such as, for example, alkaline and alkaline-hearth hydroxides, ammonium hydroxide, and amines, including heterocyclic amines.
• acids both inorganic and organic, such as, for example, hydrochloric acid, sulphuric acid, acetic acid, or, in the case of an acid group, such as carboxyl, salts with pharmaceutically acceptable bases, such as, for example, alkaline and alkaline-hearth hydroxides, ammonium hydroxide, and amines, including heterocyclic amines.
• One first group of preferred compounds comprises formula (I) compounds in which the lactone ring is 7- or 8-membered, particularly 7-membered.
• a second group of preferred compounds comprises formula (II) compounds in which the lactone ring is 5-membered.
• R 4 is different from hydrogen, and particularly a straight or branched C1-C5 alkyl or C1-C5 alkenyl or C3-C10 cycloalkyl, or (C3-C10) cycloalkyl - (C1-C5) alkyl group, or a straight or branched C ⁇ -Ci4 aryl, or (C ⁇ -Cu) aryl - (C1-C5) alkyl group, or a straight or branched heterocyclic or heterocyclo - (C1-C5) alkyl group, said heterocyclic group containing at least one heteroatom selected from an atom of nitrogen, optionally substituted with a (C1-C5) alkyl group, and/or of oxygen and/or of sulphur; said alkyl, alkenyl, cycloalkyl, aryl, aryl-alkyl, heterocycle or heterocycl
• Re and R 7 which may be the same or different, are straight or branched (C1-C5) alkyl; the — COOH group or one of its pharmaceutically acceptable esters; or the — CONRSR ⁇ group, where Re and R9, which may be the same or different, are hydrogen, straight or branched (C1-C5) alkyl, according to the definitions outlined above as examples.
• An initial group of particularly preferred compounds consists of formula (I) compounds, with a 7-membered lactone ring, and, among these, particularly:
• R,S-7-(l-t- butoxy)iminomethyl-homocamptothecin ST2127)
• R,S-7-benzyl- oxyiminomethyl-homocamptothecin ST2143
• a second group of particularly preferred compounds consists of formula (II) compounds, with a 5-membered lactone ring and with the same meanings of Ri as in the preceding group.
• compounds of general formula (I) are envisaged, where the lactone ring is 7- or 8-membered.
• compounds of general formula (II) are envisaged, where the lactone ring is 5- membered.
• the formula (I) compounds can be prepared with the process described here below and exemplified for the preferred compounds according to the present invention.
• the starting compound is camptothecin, optionally substituted in positions 8 and 9 according to the meanings of the R2 and R3 groups envisaged above.
• camptothecin is reacted with the desired alcohol, which can also be used as a reaction medium, in the presence of a mineral acid, such as, for example, sulphuric acid, and a suitable oxidising system, such as iron sulphate/hydrogen peroxide, then a further oxidising agent, such as manganese dioxide to obtain 7-(dialkoxymethyl)camptothecin.
• a mineral acid such as, for example, sulphuric acid
• a suitable oxidising system such as iron sulphate/hydrogen peroxide
• Camptothecin, or its 7-(dialkoxymethyl)-derivative are subjected to selective reduction of the carbonyl in position 19, to obtain the corresponding 19,20-dihydroxy derivative.
• the reduction is carried out in the presence of a reducing agent, for example, mixed hydrides of Al or B and exemplified in the scheme by sodium borohydride, from 1 to 10 equivalents in the presence of an alcoholic solvent for a period of time ranging from 1 to 16 h at a temperature ranging from room temperature to 50°C.
• a reducing agent for example, mixed hydrides of Al or B and exemplified in the scheme by sodium borohydride, from 1 to 10 equivalents in the presence of an alcoholic solvent for a period of time ranging from 1 to 16 h at a temperature ranging from room temperature to 50°C.
• the solvent is subsequently evaporated and the crude product is used in the subsequent step, where the E ring, in the form of the 19,20-dihydroxy derivative, is subjected to opening with from 1 to 10 equivalents of an oxidising agent, such as, for example, periodate or lead acetate.
• an oxidising agent such as, for example, periodate or lead acetate.
• the reaction is conveniently carried out in an organic solvent, such as, for example, toluene, methylene chloride or acetic acid, for a time period ranging from 1 to 24 h, at a temperature ranging from room temperature to 50°C.
• the solvent is removed in vacuo and the product is finally purified by chromatography or some other equivalent means.
• the intermediate product thus obtained is in turn dissolved in a suitable solvent medium, preferably a mixture of solvents, and then subjected to the well known Reformatsky reaction, in which the ⁇ -bromocarboxylic acid is suitably selected as a function of the n value envisaged in formula (I) or (II).
• the product of the Reformatsky reaction after being dissolved in a mixture of organic solvents, such as methylene chloride, acetic acid, and acetonitrile, is treated with from 1 to 10 equivalents of an oxidising agent (for example, chromic acid, pyridinium dichromate — PDC — manganese oxide, Na2Ru0 4 ) at a temperature ranging from 0°C to the boiling point of the solvent, for a time period ranging from 30 minutes to 24 h.
• an oxidising agent for example, chromic acid, pyridinium dichromate — PDC — manganese oxide, Na2Ru0 4
• the solvent is then removed in vacuo and the product purified by chromatography.
• the resulting compound is dissolved in a suitable organic solvent, such as, for example, methylene chloride) or an aqueous solvent and subjected to acid hydrolysis with an organic or inorganic acid, such as trifluoroacetic acid, hydrochloric acid, or perchloric acid) for a time period ranging from 1 to 24 h at a temperature ranging from 0°C to the boiling point of the solvent.
• an organic or inorganic acid such as trifluoroacetic acid, hydrochloric acid, or perchloric acid
• the latter is then removed and the product isolated by crystallisation.
• the product is finally reacted with the hydroxylamine NH2OR4 as seen above.
• formula (II) compounds, where Z is hydrogen are desired, the compound obtained by the process described here above will be subjected to suitable treatment to release the carboxylic function according to conventional ester hydrolysis methods with which the experts in the field are fully
• the compounds described in the present invention are topoisomerase I inhibitors and therefore are useful as medicaments, particularly for the treatment of diseases that benefit from the inhibition of said topoisomerase.
• the compounds according to the present invention display antiproliferative activity and are therefore used on account of their therapeutic activity and possess physicochemical properties that make them suitable for formulation in pharmaceutical compositions.
• compositions contain at least one formula (I) and/or formula (II) compound as an active ingredient, in an amount such as to produce a significant therapeutic effect.
• the compositions covered by the present invention are wholly conventional and are obtained with methods which are common practice in the pharmaceutical industry. According to the administration route opted for, the compositions will be in solid or liquid form, suitable for oral, parenteral, or intravenous administration.
• the compositions according to the present invention contain, along with the active ingredient, at least one pharmaceutically acceptable vehicle or excipient. Particularly useful may be formulation coadjuvants, such as, for example, solubilisers, dispersant agents, suspension agents and emulsifiers.
• formula (I) compounds can also be used in combination with other active ingredients, such as, for example, other anticancer drugs or other drugs with antiparasitic or antiviral activity, both in separate and in single dosage forms.
• the compounds according to the present invention are useful as medicaments with anticancer activity, for example, in lung cancers, such as non-microcytoma lung cancer, or in colorectal or prostate tumours or gliomas.
• the cytotoxic activity of the compounds according to the present invention has been assayed in cell systems of human tumour cells, using the antiproliferative activity test as the method of evaluating the cytotoxic potential.
• the cell line used is a non-microcytoma pulmonary adenocarcinoma called NCI H460, belonging to the NSCLC (non small cell lung cancer) class.
• NCI-H460 non-microcytoma lung cancer cell line
• the cells were seeded in a volume of 250 ⁇ l in 96-well plates and incubated for 24 h at 37°C. The next day the study compounds were added at scalar concentrations from 1 ⁇ M to 0.004 ⁇ M, and the cells were incubated for another 2 h at 37°C in a humidified atmosphere containing 5% CO2. The cells were washed 3 times, overturning the plates each time and adding PBS. 200 ⁇ l/well of RPMI 1640 medium containing 10% FCS were added and the plates were incubated at 37°C for a further 72 h. On day 5, the growth medium was removed by overturning the plates, and 200 ⁇ l/well of PBS and 50 ⁇ l of 80% cold TCA were added.
• the plates were then incubated in ice for at least 1 h.
• the TCA was removed by overturning; the plates were washed 3 times by immersion in distilled water and dried first on blotting paper and then under a hot air jet.
• 200 ⁇ l of 0.4% sulforodamine B in 1% acetic acid were added to all wells.
• the plates were incubated at room temperature for a further 30 minutes.
• the sulforodamine B was removed by overturning; the plates were washed by immersion 3 times in 1% acetic acid and then dried first on blotting paper and then with a jet of hot air.
• 200 ⁇ l of Tris base 10 mM were added to all wells and the plates were subjected to stirring for at least 20 minutes.
• the optical density was measured using a Multiskan spectrophotometer at 540 nm.
• Table 1 presents the IC50 values, that is to say the concentration capable of inhibiting 50% of cell survival, for each compound examined, processed using ALLFIT software.
• the suspension was then filtered through a layer of Celite placed on a Gooch filter.
• the filtered solution was concentrated to 25 ml and then poured into a solution of NaHC03 in water so as to obtain a solution at pH 6.
• the precipitate was filtered and purified on a silica gel chromatography column (eluents: CH2CI2/MEOH 99/1). 1.02 g (2.42 mmol, 55%) of product were obtained as a yellow solid.
• Rf 0.5 (CH 2 Cl 2 /MeOH 92/8).
• T 22°C; ⁇ 360 nm UV detector.
• the S configuration was attributed to A ST2523 by analogy with the camptothecins with negative [ ⁇ ]D.
• R f 0.48 (CH 2 Ci2/MeOH 95/5).
• R f 0.5 (CH 2 Cl 2 /MeOH 95/5).
• R f 0.25 (CH 2 Ci2/MeOH 95/5).

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